Metabolic syndrome is emerging as a global epidemic. The profound metabolic dysregulation in this syndrome is typically manifested by clustering of several disorders, including obesity, type 2 diabetes, and dyslipidemia, and is associated with an increased risk for cardiovascular disease. Hepatic lipogenesis and lipoprotein metabolism are important in maintaining lipid homeostasis. There is increasing evidence that hepatic lipid metabolism plays an important role in the pathogenesis of key aspects of metabolic syndrome, including hyperlipidemia, hyperglycemia, and insulin resistance. We have recently demonstrated that transcriptional coactivator PGC-1? coordinately regulates lipogenesis, lipid trafficking, and lipoprotein metabolism in the liver. These data suggest that PGC-1? is a central component of the regulatory network in maintaining lipid homeostasis. The major goals of this proposal are to test the hypothesis that PGC-1? is involved in the pathogenesis of metabolic syndrome and serves as a molecular link between lipid metabolism and insulin resistance. In addition, molecular components of the PGC-1? pathway will be dissected and analyzed. Aim 1 is to determine evaluate the role of PGC-1? in the pathogenesis of metabolic dysregulation and in linking lipid metabolism to insulin resistance. Aim 2 is to define transcriptional components underlying PGC-1? regulation of triglyceride and lipoprotein metabolism. Aim 3 is to investigate the role of chromatin remodeling in lipid metabolism. Completion of this proposal will define the molecular details of a major regulatory network in the maintenance of lipid homeostasis.